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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_4473_Библиотеки_им_академика_М_И_Перельмана
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(OD492)
mean ± SD
(OD492)
=
mean ± SD
7 Macrophage andMast Cell
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0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
IgE
∗
∗
0
Naive
OK–432
PBS Naive OK–432 PBS Naive
0.8 0.4
1.8
∗
∗
1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0
IgG
1
∗
∗
∗
∗
0.3
0.2
0.1
0
IgG
∗
OK–432 PBS
:C3H/HeN (n = 5)
:C3H/HeJ (n = 5)
2a
∗
*p < 0.005
∗
∗
Fig. 7.5 Antigen-specic Th1 and Th2 antibody in serum of C3H/HeN and C3H/HeJ mice after systemic sensitization
with OVA and CFA
IgG
0.5 1.4
0.4
0.3
0.2
0.1
0
Naive OK–432 PBS Naive OK–432 PBS Naive OK–432 PBS
IgE
∗
∗
∗
∗
∗
1.2
1.0
0.8
0.6
0.4
0.2
0
1
0.7
∗
∗
∗
∗
∗
0.6
0.5
0.4
0.3
0.2
0.1
0
IgG
∗
:wild type (n = 5)
:TLR2 ko (n
2a
∗
*p < 0.005
∗
∗
∗
5)
Fig. 7.6 Antigen-specic Th1 and Th2 antibody titers in sera of TLR2 knockout and wild-type mice
quently suppress Th2-mediated allergic inammation in nasal mucosa (Fig.7.7).
7.3.2 Regulatory Role ofLymphoid
Chemokines CCL19 andCCL21
intheControl ofAllergic
Rhinitis
The lymphoid chemokines CCL19 and CCL21 are
known to be crucial both for lymphoid cell trafcking and for the structural organization of lym-
phoid tissues such as nasopharynx-associated
lymphoid tissue (NALT). However, their role in
allergic responses remains unclear, and so our current study aims to shed light on the role of CCL19/
CCL21 in the development of allergic rhinitis.
After nasal challenge with OVA, OVA- sensitized
plt (paucity of lymph node T cells) mice, which
are decient in CCL19/CCL21, showed more
severe allergic symptoms than did identically
treated wild-type mice [22] (Fig. 7.8). OVAspecic IgE production, eosinophil inltration,
and Th2 responses were enhanced in the upper air-
84
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H. Kawauchi
Fig. 7.7 Summary of the effect of OK-432, which is a
potent Th1 inducive biological response modiers, on the
murine allergic rhinitis model. (1) OK-432 seems to
induce IL-12 production from macrophages via TLR2 and
activate Th1 response and consequently downregulate
antigen-specic Th2 response. (2) Prophylactic treatment
with like as OK-432 (Th1 inducer) may be anticipated to
regulate the induction phase of type-I allergic response
Fig. 7.8 Features of plt (paucity of lymph node T cells) mice
way of plt mice. Moreover, in plt mice, the number
of CD4+CD25+ regulatory T cells declined in the
secondary lymphoid tissues, whereas the number
of Th2-inducer-type CD8+CD11b+ myeloid dendritic cells (m-DCs) increased in cervical lymph
nodes and NALT. Nasal administration of the
plasmid- encoding DNA of CCL19 resulted in the
reduction of m-DCs in the secondary lymphoid
tissues and the suppression of allergic responses in
plt mice. These results suggest that CCL19 and
a
IL
–
–
–
–
4IL5 IL 13 IFN
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CCL21 act as regulatory chemokines for the control of airway allergic disease and so may offer a
new strategy for the control of allergic disease. In
a different study to focus on dendritic cells of
regional lymph node, we constructed an effective
murine model of sublingual immunotherapy
(SLIT) in allergic rhinitis, in which mice were sublingually administered with ovalbumin (OVA) followed by an intraperitoneal sensitization and nasal
challenge of OVA [20]. Sublingually treated mice
showed signicantly decreased allergic responses
as well as suppressed Th2 immune responses
(Fig.7.9). Sublingual administration of OVA did
not alter the frequency of CD4+CD25+ regulatory
T cells (Tregs), but led to the upregulation of
Foxp3- and IL-10-specic mRNAs in the Tregs of
cervical lymph nodes (CLN), which strongly suppressed Th2 cytokine production from CD4+CD25effector T cells invitro. Furthermore, sublingual
administration of plasmids encoding the lymphoid
chemokines CCL19 and CCL21-Ser DNA
together with OVA suppressed allergic responses
(Fig.7.10) [23]. These results suggest that IL-10expressing CD4+CD25+Foxp3+ Tregs in CLN are
involved in the suppression of allergic responses
and that CCL19/CCL21 may contribute to it in
mice received SLIT (Figs.7.11a–c).
To summarize our recent data, the important
regulatory role of macrophage or dendritic cells
and their interaction with T cells in nasal mucosa
and its regional lymphoid organ are extensively
demonstrated in accordance with human studies
on these cells. However, further extensive basic
and clinical research is required for pursuing the
ideal treatment strategy.
Effect of Lipopolysaccharide (LPS) on
Eliciting Phase of Murine Allergic Rhinitis
Model in Relation with Toll-Like Receptor
Mast cells which are the key player at the eliciting phase of allergic rhinitis have been reported
OVA 500
(D56)(D63)(D70)
g sl.
OVA 400 g in.OVA 25 g/Alum 1 mg ip. OVA 400 g in.
(Day0)(D 7)(D14) (D 21~34) (D 77~90)
7,000
6,000
5,000
4,000
3,000
2,000
–
1,000
OVA specific IgE(ng/ml)
b
PBS PBS OVAPBS OVAPBS OVAPBS OVAOVA
6,000
5,000
4,000
3,000
(pg/ml)
2,000
1,000
**
*
00
Fig. 7.9 Antigen-specic serum IgE production and Th1/
Th2 prole in spleen of mice which received therapeutic
sublingual OVA treatment after induction of allergic rhinitis. Mice were sublingually administered with either PBS
or OVA after intraperitoneal sensitization and nasal challenges with OVA.Thereafter, the mice received consecutive nasal challenges with OVA again and examined for
their allergic responses. (a) OVA-specic IgE levels in
serum were assayed by sandwich ELISA. (b) Culture
supernatants of CD4+T cells of spleen obtained from sublingually treated mice with allergic rhinitis were assessed
for Th1 and Th2 cytokine production levels by
ELISA.These data are representative of two independent
experiments containing three to ve mice in each group.
Signicance was evaluated by an unpaired t test.
*p<0.05, **p<0.01
86
a
OV
OV
OVA−specific IgE(ng/ml)
**
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H. Kawauchi
PBS OVA
29]. However, it is still controversial that LPS
effect on the eliciting phase of allergic inamma-
CCL19
tion. Therefore, we investigated the LPS effect on
the eliciting phase of murine allergic rhinitis
CCL21
model.
As recently reported by Aoi et al., in our
GAPD
b
murine allergic rhinitis model, LPS instillation
into the nasal cavity with ovalbumin (OVA)
resulted in exacerbated nasal symptom and
eosinophil inltration of wild type of mice (LPS-
1. 400
1. 200
responsive BALB/c strain) [30]. On the other
hand, nasal symptom and eosinophil inltration
*
were evident in C3H/HeN (LPS-responsive)
mice, but neither in C3H/HeJ (LPS-non-
1. 000
responsive) mice, nor mast cell-decient
WBB6F1 W/Wv mice. IL-5 production by mast
800
600
400
cells in the nasal mucosa of wild type of mice
(BALB/c) was enhanced by LPS co-instillation.
But it was enhanced neither in those of C3H/HeJ
mice nor WBB6F1 W/Wv mice. These data
obtained with mast cell-decient WBB6F1 W/
200
0
OVA
PBS
pCCL19
pCCL21
A+pCCL19
A+pCCL21
Wv mice may indicate that LPS aggravated nasal
symptom, upregulating Th2 cytokine production
of mast cells via TLR4.
Therefore, we are summarizing our experimental data as follows. LPS instillation into nasal
cavity, at the eliciting phase of murine model of
Fig. 7.10 Chemokine expression in CLN of sublingually
treated mice and the effect of sublingual administration of
pCCL19/pCCL21 with antigen on Th2-mediated allergic
responses. (a) Semiquantitative RT-PCR was performed
to assess mRNA expression pattern of chemokines,
CCL19 and CCL21in whole cells isolated from CLN of
mice sublingually treated with either PBS or OVA. (b)
Mice were sublingually administered with either PBS,
OVA alone, 100mg of pCCL19 together with OVA, and
100mg of pCCL21 with OVA for total three times before
systemic sensitization and nasal challenge. OVA-specic
IgE levels in serum were assayed by sandwich ELISA
allergic rhinitis, actually exacerbates nasal symptom, which is accompanied by mast cell activation and enhanced Th2 responses. These
observations can be extrapolated into the human
condition with better understanding the mechanisms of bacterial infection-induced exacerbation
of the clinical features of allergic rhinitis.
However, LPS concentration should be taken into
account how does it affect on the nasal symptom
at the eliciting phase as well as the induction of
allergic rhinitis. Most our recent experimental
to produce Th2 cytokines invitro with lipopolysaccharide (LPS) stimulation via TLR4, but
invivo study remains to be performed [24, 25].
As it is reported in the hygiene hypothesis that
neonatal exposure with LPS prevents allergic airway diseases, allergic inammation is generally
reported to be downregulated at the induction
phase with the existence of bacterial LPS [26–
data came to the conclusion that a low dose of
LPS at eliciting phase of allergic rhinitis can
exacerbate allergic nasal symptom but high dose
of LPS at eliciting phase of allergic rhinitis conversely downregulate nasal allergic symptom
(Unpublished data). So, mast cell can be concluded also the key player as well as macrophage
to modify upper respiratory allergic reactions.
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a
87
b
Fig. 7.11 (a) Chemokine receptor CCR7 and its ligands
CCL19 and CCL21 are involved in the chemotaxis of T cells
and DCs. (b) In steady state, naturally occurring Tregs have
inhibitory effects to the interaction of naïve T cells and
m-DCs for the suppression of excessive Th2 differentiation
to inhaled allergen. (c) The deciency of CCL19/CCL21
somehow inhibits the accumulation of Tregs, which work as
suppressor of Th2 environment induced by m-DCs in the
secondary lymphoid tissues, resulted in the establishment of
Th2-dominant allergic disease
88
c
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Fig. 7.11 (continued)
H. Kawauchi
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The Neutrophil andChronic
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Rhinosinusitis
MartinY.Desrosiers andShaunJ.Kilty
8
Core Messages
• Chronic rhinosinusitis (CRS) is a complex
heterogeneous inammatory disease that has
traditionally been characterized as primarily
“eosinophilic” in nature but in which contributions from other cell types may lead to different sub-phenotypes of disease.
• Neutrophils are key inammatory cells in the
immune response, and while their role is less
well understood in CRS, it may nevertheless
be signicant.
• A better understanding of neutrophilic inammation in CRS could lead to the development
of new therapeutic strategies for CRS.
Descriptions of chronic rhinosinusitis (CRS) are
frequently characterized by references to the
eosinophilia present in CRS and in allergic diseases. However, the focus in the assessment of
inammation in chronic rhinosinusitis is increasingly shifting away from Th2-dominated mechanisms to a consideration of the contributions by
Th1 and Th17 mechanisms as well. This has led
M. Y. Desrosiers
Division of Otolaryngology—Head and Neck
Surgery, Université de Montréal/Centre Hospitalier
de l’Université de Montréal (CHUM) Hôpitale
Hôtel-Dieu de Montréal, Montréal, QC, Canada
S. J. Kilty (*)
Department of Otolaryngology—Head and Neck
Surgery, The University of Ottawa/The Ottawa
Hospital, Ottawa, ON, Canada
to an increased focus of interest in the assessment
of lymphocyte subpopulations and of cytokines
associated with these inammatory pathways.
Throughout this, the neutrophil, a somewhat
ubiquitous inammatory cell associated with
both Th1 and Th17 patterns of inammation, has
been somewhat ignored. In this chapter, we
review the structure and function of the neutrophil and review evidence for its potential implication in chronic rhinosinusitis.
8.1 Histologic Description
Neutrophils are the most abundant leukocyte in
humans representing up to 60% of the circulating
white blood cells. It is a member of the family of
granulocytes, which also includes basophils and
eosinophils. Neutrophils are considered an essential component of the innate immune system by
virtue of their multiple actions in bacterial killing
and sequestration. Neutrophils cause microbial
death by three means: phagocytosis, by generating neutrophil extracellular traps (NETs), and
through the release of soluble antimicrobials
from their primary and specic granules [1].
Neutrophils derived their name from their differential response in staining from other granulocytes with hematoxylin and eosin or Wright’s
Giemsa staining. Eosinophils intensely capture
eosin, giving them their characteristic appearance
under the microscope. The abundant azurophilic
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023
Ö. Ö. Celebi, T. M. Önerci (eds.), Nasal Physiology and Pathophysiology of Nasal Disorders,
https://doi.org/10.1007/978-3-031-12386-3_8
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Fig. 8.1 Neutrophil on blood smear, Wright’s Giemsa
stain. Original magnication 100× oil immersion. Note
the characteristic multi-segmented nucleus and mostly
lilac-staining specic (secondary) granules and a few azurophilic primary granules. Surrounding cells are mature
erythrocytes. (Credit: Ruth F. Padmore MD, FRCPC,
PhD, Ottawa, Canada)
granules of the basophils give them a bluish hue.
The neutrophil is instead characterized by the
neutral aspect of its cytoplasmic staining and its
multiply segmented nucleus (Fig.8.1).
Neutrophils have a diameter of 12–15μm. In
circulating blood, neutrophils are in a quiescent,
or resting state, and have a vaguely circular form.
However, when activated, the shape changes,
with the cell becoming more amoeba-like, with
pseudopods extending in search of antigens.
The granules present in neutrophils contain a
number of substances with either bactericidal or
proteolytic actions. Primary (azurophilic) granules typically contain the bactericidal enzyme
defensins and cationic proteins. They also contain proteolytic enzymes, cathepsin G, lysozyme,
and myeloperoxidase. The specic (secondary)
granules contain lysozyme, lactoferrin, as well as
compounds involved in the formation of toxic
oxygen species [2].
8.2 Hematologic Progenitors
As granulocytes, neutrophils share their origins
with basophils and eosinophils. These are
derived from progenitor cells in the bone mar-
M. Y. Desrosiers and S. J. Kilty
row and then differentiate through myelocytes
into promyelocytes and then into the nal differentiated cell.
Neutrophils have a relatively short half-life,
up to 6days. This is believed both to prevent the
spread of pathogens that may parasitize within
neutrophils to facilitate survival and dispersion
and also to limit local tissue damage caused by
the intense antibacterial activity of the neutrophil
in a tissue.
8.3 Physiology andFunction
Neutrophils are principally responsible for bacterial killing, which they enact through a variety of
mechanisms. Prior to serving this role, neutrophils are primarily present in the circulation in an
inactivated form. They then migrate into target
tissues to exert their effects following activation
by a variety of pro-inammatory signals.
The transit from the bloodstream to tissue
begins with a process called diapedesis. This leukocyte extravasation process occurs when the
activated neutrophil approaches the periphery of
the blood vessel and then becomes attached to
and migrates through the blood vessel wall in a
process called diapedesis. This involves an interaction with receptors called intracellular adhesion molecules (ICAMs) and various selectins
and integrins.
Arrived at the site of infection, the neutrophil
exerts its antibacterial action through the following mechanisms:
1. Phagocytosis and killing of pathogens.
2. Neutrophil extracellular trap (NET).
3. Protease digestion through the release of
granule contents.
The activated neutrophil can phagocytose bacteria by engulng them and killing them within
the cell through the generation of toxic substances. This process called the “oxidative burst”
creates a high concentration of reactive oxygen
species (ROS) through a process involving
NADPH oxidase activation and the creation of
superoxide dismutase (SOD). Through several
steps, this leads to the production of hypochlo-
8 The Neutrophil andChronic Rhinosinusitis
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93
rous acid (HClO), which may be bactericidal in
itself and/or lead to the activation of the necessary proteases [3].
More recently, a role for extracellular trapping and killing of bacteria by neutrophils has
been described by the formation of “extracellular NETs.” In this mechanism, neutrophils
secrete a mesh composed of DNA and various
proteins outside the neutrophil, which serves to
trap and destroy bacteria (Fig. 8.2). This may
also limit the propagation of infection as well.
NETs which form intravascularly are responsible for many of the clinical manifestations of
sepsis.
The neutrophil also plays a role in limiting
potentially negative effects of inammation
through the secretion of various serine proteases.
The most well known of these is alpha-1antitrypsin, which serves to limit the extent of
damage caused by neutrophil elastase released
from granules in tissue. Individuals with low levels of alpha-1-antitrypsin may have inordinate
responses to trauma. In smokers, this may lead to
the development of emphysema.
8.4 Implication inDisease
Low levels of circulating neutrophils, or neutropenia, may occur from genetic causes or from
infectious or toxic causes, one of which the most
familiar is chemotherapy. Individuals with neutropenia are particularly susceptible to infection
by bacterial pathogens.
The neutrophil may also be involved primarily in
inammatory diseases. Familial Mediterranean
fever is a relapsing disorder where individuals present with bouts of acute inammation characterized
by hyperthermia, arthralgia, and peritonitis. Due to
a dysfunction in the MEFV gene, individuals have a
reduced amount or structural malformations of a
protein called pyrin which makes up part of the
cytoskeleton of leukocytes. Pyrin abnormalities
lead to defective inammation regulation and, subsequently, to inappropriate or prolonged inammatory activity [4]. It is a disorder not directly linked to
neutrophil level, but rather to function, as described
for alpha- 1- antitrypsin deciency above.
8.5 Implications inRespiratory
Disease
Fig. 8.2 Neutrophil extravasation trap (NET). In this
scanning electron microscope image, an Anthrax bacteria
(orange) is being engulfed by a single neutrophil (yellow),
by the generation of a NET. (By Volker Brinkmann [CCBY- 2.5 (http://creativecommons.org/licenses/by/2.5)], via
Wikimedia Commons)
While interest in the role of granulocytes in the
development of chronic respiratory disease has
principally focused on the role of the eosinophil
in the pathogenesis of asthma, evidence is
increasing to support the role of the neutrophil in
the development of both asthma and chronic
obstructive pulmonary disease.
Assessment of a large cohort of individuals
with hard-to-treat asthma has identied phenotypes characterized by neutrophilic inammation
in expectorated sputum. This has led to a consideration of neutrophilia in the pathogenesis of steroid resistance in asthma [5, 6].
The neutrophil has also been implicated in
chronic obstructive pulmonary disease. Apart
from alpha-1-antitrypsin deciency, as mentioned
above, neutrophil elastase has been shown to be
increased in individuals with COPD [7]. This is
even more pronounced in individuals with COPD
and also presents symptoms of bronchitis.
Experimental evidence implicating the neutrophil
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